Journal of Antimicrobial Chemotherapy (2001) 47, 819-827
© 2001 The British Society for Antimicrobial Chemotherapy
Erythrocyte-mediated delivery of a new homodinucleotide active against human immunodeficiency virus and herpes simplex virus
a Institute of Biochemistry ‘G. Fornaini’ and d Institute of Hygiene, University of Urbino, 61029 Urbino; b Department of Chemical Science, University of Camerino, 62032 Camerino; c Department of Experimental Medicine, University of Rome ‘Tor Vergata’, 00133 Rome; e IRCCS ‘L. Spallanzani’, 00173 Rome, Italy
Monocyte-derived macrophages (MDMs) play a central role in the pathogenesis of infection by human immunodeficiency virus (HIV-1) and represent one of the main reservoirs of the virus in the body. In addition, MDMs can easily be infected by various herpes viruses, including herpes simplex virus type 1 (HSV-1). We have synthesized a new antiviral agent (Bis-PMEA) that consists of two 9-(2-phosphonylmethoxyethyl)adenine (PMEA) molecules bound by a phosphate bridge. This nucleotide analogue, like the parent compound PMEA, has strong and selective activity against HIV-1 and HSV-1. A drug-targeting system previously developed in our laboratory was used for the selective delivery of these drugs to macrophages. Bis-PMEA and PMEA were encapsulated into autologous erythrocytes by a procedure of hypotonic dialysis and isotonic resealing. Loaded erythrocytes were modified to increase their recognition and phagocytosis by human macrophages. By administering Bis-PMEA-loaded erythrocytes to macrophages, 47% of Bis-PMEA and 28% of PMEA was still present 10 days after phagocytosis; in contrast, only 12% of PMEA was found in macrophages receiving PMEA-loaded erythrocytes. Bis-PMEA-loaded erythrocytes were then added to macrophages infected with HIV-1 and HSV-1 and their antiviral activity evaluated. Remarkable protection was obtained against HIV-1 and HSV-1 infection (95 and 85%, respectively). Therefore, Bis-PMEA acts as an efficient antiviral prodrug that, following selective targeting to macrophages by means of loaded erythrocytes, can protect a refractory cell compartment.
* Correspondence address. Istituto di Chimica Biologica ‘G. Fornaini’, Università degli Studi di Urbino, Via Saffi, 2-61029 Urbino, Italy. Tel: +39-0722-305211; Fax: +39-0722-320188; E-mail: magnani{at}bib.uniurb.it
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